One person has died, and five others were hospitalized, after a clinical trial of an experimental drug in France went tragically wrong. But days after the first public acknowledgement of the incident on 15 January, a lack of official information has left outside experts and the public largely in the dark as to what happened.

"The French authorities have not been very rapid nor transparent in their response," says Catherine Hill, an expert in clinical-trial design and a former member of the scientific advisory board of France’s National Agency for Medicines and Health Products Safety (ANSM). She adds that French investigations into other medical accidents have often been opaque.

The trial was a 'first in human' phase I trial to test the safety of the drug in healthy people. The Portuguese company Bial produced the drug, which was aimed at treating anxiety and motor disorders associated with Parkinson's disease, and chronic pain in people with Alzheimer's disease, cancer and other conditions. Biotrial, a French contract research organization, conducted the trials at its clinical facilities in Rennes.

But a lack of information leaves many key questions unanswered, says Marc Rodwin, an expert on biomedical law at Suffolk University Law School in Boston. This includes how the subjects’ injuries came about—MRI scans showed deep necrotic and haemorrhagic lesions in the brain—and whether the trials were conducted properly.

Brain enzyme
In particular, neither the French authorities, nor BioTrial, has disclosed the identity of the molecule given in the trials. Bial did disclose that the drug was an FAAH (fatty acid amide hydrolase) inhibitor. FAAH is an enzyme produced in the brain, and elsewhere in the body, that breaks down neurotransmitters known as endocannabinoids. By blocking these enzymes, FAAH inhibitors cause endocannabinoids—which activate the same neural receptors as a chemical in cannabis and may have analgesic properties—to accumulate in the body.

Some scientists scrambled over the weekend to try to establish the identity of the drug. Among them were Stephen Alexander, a molecular pharmacologist at the University of Nottingham Medical School, who has worked on FAAH for 15 years, and his colleague Christopher Southan, a pharmacologist and curator of the University of Edinburgh's Guide to Pharmacology. Together, the pair examined an online list of drugs in the company's research pipeline.

This revealed just two molecules in phase I trials, one of which best fitted the therapeutic profile mentioned by Bial, although it was only referred to by a codename, BIA 10-2474. A French newspaper also published a recruitment form given to a volunteer in the trial that mentioned a drug with the same codename. “As best as we can make out, this compound has not been described in the [scientific] literature,” says Alexander. “So we’re working in the dark.”

It is common in the pharmaceutical industry not to reveal the structure of a molecule this early in development—although this practice has been criticized by researchers. “They declare code names of candidates in development and hide the structure," says Southan. "I think it’s time they stopped." This left researchers over the weekend trying to second-guess the likely structure from published Bial patents, Southan adds. He also says that there seems to be no entry for the trial in clinical trial registries.

Radioactive label
Numerous companies have developed FAAH inhibitors. There are none on the market, as most clinical trials have shown them to be ineffective—but the ones that were previously tested proved safe.

Many researchers believe that BIA 10-2474 is acting on an ‘off target’—in other words, inhibiting a protein other than an FAAH. There are experiments that could determine which other proteins the compound binds in addition to FAAH, in particular by radioactively labelling the compound and then using it to ‘fish out’ the proteins it binds to from post-mortem human brain tissue.

Knowing the drug's molecular structure would also enable scientists to run computer predictions of this and other mechanisms that might result in toxicity. “There’s a whole gamut of sophisticated computation analysis to predict anything you like," says Southan.

Other researchers studying the FAAH pathway may look more closely at the potential for inhibitors to strike other proteins. “I think it’s very likely that both private industry and academic institutions will be looking very hard as to what this off target affect might be," says Alexander.

The lack of transparency is typical of French investigations, which tend to favour secrecy until firm conclusions are established, says a French expert on health law who requested anonymity. He notes that the rules in France governing research on human subjects are strong and guarantee substantial protection of trial participants. And he adds that safety incidents in clinical trials are next to unheard of there, with the price often being delays in the approval of trial applications.

Streamlined rules
In recent years, there have been two major changes to French laws affecting the approval of drugs in clinical trials. The country strengthened its medical safety laws following the withdrawal in 2009 of a diabetes drug that was suspected of causing hundreds of deaths: the 2011 Sunshine law, in particular, tightened rules on conflicts of interest for experts taking part in the country's drug approval process, as well as allowing for more safety testing of medications after approval. Then in 2012, the government passed a separate law that was intended to streamline the rules for research involving human subjects in order to make France more attractive to companies for clinical trials.

One possible safety issue in the trial of BIA 10-2474, notes Hill, is that all six trial participants were administered the doses simultaneously, rather than testing in one and waiting to check for adverse effects before administering to further subjects.

Simultaneous rather than sequentialadministration was identified as problematic in a distastrous UK clinical trial in 2006 that caused multiple organ failure in six participants. "From the 2006 catastrophe in London, I had concluded that treating several individuals with the same dose on the same day in a phase I trial was a big mistake," she says.

Jean-Marc Gandon, the president and chief executive of Biotrial says he is unable to immediately respond to queries put to Biotrial by Nature, and says that his time is focused on trying to save the patients, but that the company will respond later.

Bial spokeswoman Susana Vasconcelos says that the trials had been conducted "in accordance with all the good international practices guidelines, with the completion of tests and preclinical trials" and that the company "is committed to determine thoroughly and exhaustively the causes which are at the origin of this situation".

Ninety received different doses of the drug, and the remainder a placebo.

The trial had tested escalating single doses of the drug without observing any serious adverse side effects.

The six trial subjects who fell ill were the first to receive repeat higher doses over the course of several days.

The first subject to fall ill experienced adverse symptoms on 10 January and died on 17 January.

Biotrial halted the trial on 11 January; the other five subjects to fall ill were hospitalized in the days that followed.

One of these patients has since been discharged, and the condition of the other four is judged serious but stable.

Authorities are contacting the 84 other people who received the drug at lower doses to arrange medical check-ups; none of the 18 given neurological check-ups over the weekend showed any of the symptoms of those who fell ill.

This article is reproduced with permission and was first published on January 18, 2016.

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